The recent call for elimination of malaria caused by Plasmodium falciparum and eventual eradication of all malaria has focused attention on this disease, which is responsible for hundreds of millions of cases and a million deaths annually. An ideal tool for eliminating P. falciparum, the causative agent of 99% of all malaria deaths, would be a highly effective vaccine that prevents blood stage infection and thereby prevents all disease and transmission. When attenuated P. falciparum sporozoites (PfSPZ) are administered by the bite of infected mosquitoes, >90% of human volunteers are protected against experimental P. falciparum challenge and protection lasts at least 10 months. Sanaria's goal is to develop and commercialize an attenuated PfSPZ vaccine that prevents P. falciparum blood stage infection in >90% of recipients;a vaccine that could be used to eliminate P. falciparum from the world. This vaccine has the potential for >$1 billion annual revenues in markets in the developed and developing world. Sanaria has succeeded in accomplishing the goals of its Phase II SBIR grant, 5R44AI055229-05, including robust, reproducible, and consistent manufacture and release of clinical lots of the PfSPZ Vaccine, and in 2009 will be initiating a Phase 1 clinical trial to assess safety, immunogenicity, and protective efficacy of the PfSPZ Vaccine. After demonstrating safety in that trial, the goal is to move as swiftly as possible to safety and proof of concept efficacy studies in African adults, young children, and infants. These will be followed by additional Phase 2 studies, including dose optimization studies, and then pivotal Phase 3 studies to support licensure. Based on the results of 6 successful production campaigns under cGMPs, which have manufactured PfSPZ Vaccine for the first clinical trials, Sanaria has identified specific aspects of its manufacturing process and control assays that represent either bottlenecks or opportunities for significant improvement. The goal of this proposal is to focus on these bottlenecks and opportunities by conducting innovative research and development to establish and finalize a more efficient, scaled-up, validated manufacturing and release process for the PfSPZ Vaccine. To address this overarching goal Sanaria will reduce the quantity of blood products and personnel used for the production of gametocytes to feed to mosquitoes, increase the efficiency of mosquito production, and increase the numbers of sporozoites produced and harvested from infected mosquitoes. The increased efficiency will be accompanied by scale-up of the entire manufacturing process, and improvements in throughput, specificity and sensitivity of assays used for in process control during manufacture and release of the PfSPZ Vaccine. An essential element of this application is that all of these improvements will be validated for subsequent production of PfSPZ Vaccine under cGMPs. Success in this Phase II SBIR renewal will leave Sanaria ideally placed to design and construct a facility in which the PfSPZ Vaccine can be optimally manufactured for pivotal Phase 3 studies, licensure and commercial launch of the PfSPZ Vaccine. PUBLIC HEALTH RELEVANCE: Malaria causes 500 million clinical cases and 1-3 million deaths annually, is responsible for >1% loss of GDP in Africa annually and is a serious concern for travelers and military personnel. Sanaria's goal is to develop and commercialize a >90% protective malaria vaccine for three primary markets with a potential for >$1 billion annual revenues: 1) Travelers from the developed world to malaria endemic areas. 2) Infants and young children in the developing world. 3) Adolescent girls in the developing world. Success in this Phase II SBIR renewal will leave Sanaria ideally placed to design and construct a facility in which the company's malaria vaccine can be optimally manufactured for pivotal Phase 3 studies, licensure and commercial launch.